This study was performed to quantify the impact of Haldane effect (HE) on the relationship between O2 extraction (O2Ex; mL O2/dL blood) and venous pH in 247 measurements performed in 91 septic patients (73 patients with intra-abdominal sepsis, 11 with retroperitoneal abscesses, 6 with severe cholangitis, and 1 with gangrenous fasclitis). The severity of sepsis varied from relatively compensated to extremely diseased conditions. This allowed a detailed assessment of the impact of HE over a wide range of cardiorespiratory and metabolic abnormalities. A recently developed model was used to quantify blood CO2 exchange and Haldane relationships and, in particular, the buffering of venous pH allowed by O2Ex (O2-linked H+ binding) on the basis of arterial and mixed venous blood gas measurements. Arterio-venous pH difference (a-vDpH) was .033 +/- .024 (mean +/- SD). It increased with venoarterial CO2 concentration difference (v-aDCO2; mL CO2/dL blood), but the increase was moderated by a simultaneous increase in O2Ex, as the likely consequence of HE: a-vDpH = .006 + .017 (v-aDCO2) - .009 (O2Ex) [r2 = .96, p < < .001]. To confirm this, the moderation of a-vDpH allowed by the HE (DpH) was calculated. A first component, due to O2-linked H+ binding, had a value of .016 +/- .012, and a second component, due to the Haldane-mediated reduction in venous CO2 tension and plasma carbonic acid concentration, had a value of .019 +/- .006. Their sum (total DpH) was .033 +/- .017 and was related directly and strongly to O2Ex: DpH = -.002 + .009 (O2Ex) [r2 = .85, p < < .001], thus confirming the quantitative impact of HE in moderating the decrease in venous pH relative to arterial pH. The loss of this effect was responsible for the larger decreases in venous pH observed in hypodynamic patients developing impaired O2Ex. These results allow an easy quantification of the Haldane component, separated from the other components affecting pH, and are also useful for assessing the protective role exerted by HE against excessive decreases in venous pH in circulatory failure.